2-Cyano-2-(3-phenoxy-phenyl)-propionic acid amide and preparation thereof

ABSTRACT

2-(3-phenoxy-phenyl)-propionic acid or its pharmaceutical treatments, are prepared by hydrolyzing and partially decarboxylating ##STR1## wherein R=C 1  -C 6  alkyl or amino, the latter compounds being themselves new and, where R=C 1  -C 6  alkyl, have antiinflammatory pharmaceutical properties.

This is a division of application Ser. No. 105,988, filed Dec. 21, 1979,U.S. Pat. No. 4,304,930.

The present invention relates to a process for the preparation of2-(3-phenoxy-phenyl)-propionic acid by hydrolyzing a compound of theformula ##STR2## wherein R is C₁₋₆ alkoxy or amino, and partiallydecarboxylating same and converting the obtained compound--ifdesired--to a salt or setting it free from its salt by methods known perse.

BACKGROUND OF THE INVENTION

The anti-rheumatic activity of 2-(3-phenoxy-phenyl)-propionic acid(Fenoprofen) is known.

Several methods are disclosed for the preparation of the compound. Thecompound has been prepared for example by hydrolysis of2-(phenoxy-phenyl)-3-propionitrile with sodium hydroxide in 50% aqueousethanol for 72 hours (Swiss patent specification No. 527 155). Thestarting nitrile was prepared by methylation of m-phenoxy-acetophenonefollowed by reduction to α-methyl-3-phenoxy-benzyl alcohol with sodiumborohydride and followed by halogenation of the obtained product toα-methyl-3-phenoxy-benzyl bromide with phosphorus tribromide andreaction with sodium cyanide in anhydrous dimethyl sulfoxide (Swisspatent specification No. 527 155). According to another processα-methyl-α-(3-phenoxy-phenyl)-malonic acid is decarboxylated in a meltat 130°-160° C. The starting material was prepared by reactingα-(3-phenoxy-phenyl)-acetic acid diethyl ester with diethyl carbonate toobtain α-methyl-α-(3-phenoxyphenyl)-malonic acid diethyl ester which washydrolyzed in aqueous alcohol by boiling it together with sodiumhydroxide. The reaction mixture of the last step was purified by washingwith ether in order to remove the starting ester as the hydrolysis wasonly partial (Swiss patent specification No. 527 155).

Further processes comprise reacting phenoxy-phenylmagnesium bromide withthe sodium salt of 2-bromo propionic acid in ether medium (Hungarianpatent specification No. 168 376); reacting1-propynyl-3-(phenoxy)-benzene with thallium nitrate in the presence ofalcohol (Hungarian patent specification No. 173 576); oxidizing1-isobutenyl-3-phenoxy-benzene (Spanish patent specification No. 464352); and oxidizing phenoxy-phenylpropionic acid aldehyde with silveroxide (German Patent Publication No. 2 533 397).

OBJECT OF THE INVENTION

All the enumerated processes have one common disadvantage that is usingthe expensive cresol as starting material. The present invention offersan economic base for the preparation of the compounds of the formula Ifrom m-phenoxy-benzyl cyanide as starting material. The latter compoundis prepared from benzyl alcohol, by halogenation thereof and byreplacing halogen by cyano.

DESCRIPTION OF THE INVENTION

If as starting material a compound of the general formula I is employedin which R stands for amino, a very pure 2-(3-phenoxy-phenyl)-propionicacid may be prepared by a particularly simple method.

The known processes have another disadvantage that is the necessity ofan additional purification of the obtained product causing manydifficulties under industrial circumstances as the boiling point of theproduct is very high: 168°-171° C. at 0.11 mmHg. The additionalpurification of 2-(3-phenoxy-phenyl)-propionic acid is necessary in eachcase of the known processes, because the formed intermediate productsare also difficult to purify due to their high boiling point.

At the same time in pharmaceutical technology the purity of the startingmaterials is a basic requirement.

According to the present invention 2-(3-phenoxy-phenyl)-propionic acidmay be prepared from a compound of the formula I, wherein R is amino,i.e. from 2-cyano-2-(3-phenoxy-phenyl)-propionic acid amide and thus theadditional purification of the product may be avoided.2-Cyano-2-(3-phenoxy-phenyl)-propionic acid amide is a solid substancewhich may, if desired, be purified by simple crystallization and thusrather impure starting materials may also be employed and thus theprocess becomes economic.

Compounds of the formula I used as starting material in the process ofthe invention are new compounds and are also the subject of the presentinvention.

The invention also provides a process for the preparation of thecompounds of the formula I.

Compounds of the formula I are prepared by reacting m-phenoxy-benzylcyanide with C₁₋₆ dialkyl carbonate in the presence of a basic catalyst,by methylating the thus obtained new 2-cyano-2-(3-phenoxy-phenyl)-aceticacid C₁₋₆ alkyl ester and reacting optionally the obtained compound ofthe formula I, wherein R is C₁₋₆ alkoxy, with a compound suitable forthe introduction of an amino group into the molecule, preferably withammonia.

According to a preferable embodiment of the present inventionm-phenoxy-benzyl cyanide is heated with diethyl carbonate in ananhydrous organic solvent, preferably in a lower alcohol, advantageouslyin ethanol in the presence of equimolar amount of alkali alkoxide,preferably sodium ethoxide. It has been found surprisingly that thecondensation may be carried out with better results than by thegenerally used method known from the state of art of similar reactions,which comprises carrying out the synthesis by elimination of ethanol byheating with an excess of diethyl carbonate and removing the formedalcohol by a continuous azeotropic distillation (Org. Synth. Coll. Vol.IV. p. 461).

According to the present invention the reaction is carried out in ahomogeneous solution; thus the reaction time is shorter and2-cyano-2-(3-phenoxy-phenyl)-acetic acid C₁₋₆ alkyl ester is formed witha higher yield and purity. Preferably 1 to 2.5 moles of diethylcarbonate are used for 1 mole m-phenoxy-benzyl cyanide. The thusprepared 2-cyano-2-(3-phenoxy-phenyl)-acetic acid C₁₋₆ alkyl ester isseparated, if desired, or preferably treated with a methylating agentwithout isolation. As the methylating agent dimethyl sulphate or methyliodide are used. The methylating agent is used in an excess of 5 to100%. If as starting material 2-cyano-2-(3-phenoxy-phenyl)-acetic acidC₁₋₆ alkyl ester is employed, then the starting material is dissolved ina solution of sodium ethoxide, preferably in an equimolar amount inanhydrous ethanol and heated with the methylating agent.

The obtained compound of the formula I, wherein R is C₁₋₆ alkoxy, isisolated, if desired, or preferably used for the preparation of2-cyano-2-(3-phenoxy-phenyl)-propionic acid amide without isolation orpreferably by reacting it with ammonia in solution.

As a solvent organic solvents, such as alcohols, particularly methanolor ethanol, may be used. The reaction of2-cyano-(3-phenoxy-phenyl)-propionic acid alkyl ester takes place in thesolvent containing ammonia. The reaction may be carried out by heatingor without heating. The reaction may be carried out at a temperaturerange of from 0° to 150° C., preferably 20° to 100° C. The compounds ofthe formula I containing NH₂ as R, are obtained substantially withtheoretical yield, and if desired, may be simply isolated as the productcrystallizes upon cooling in the form of colorless crystals.

If the product contains impurities, it may be simply purified byrecrystallization from aqueous alcoholic solution.

The optionally isolated and purified compound of the formula I or asolution containing same are preferably hydrolyzed in water or in anaqueous organic solvent mixture in the presence of a base or an acid.One may employ mineral acids, such as sulphuric acid or hydrochloricacid, inorganic bases, such as alkali and alkali earth metal-hydroxidesor organic acids or organic bases. The reaction is preferablyaccelerated by heating. The product is obtained with nearly theoreticalyield. According to a particularly preferable embodiment of the processhydrolysis and partial decarboxylation of the compound of the formula Iis carried out by heating in an aqueous C₁₋₄ alcoholic solution in thepresence of an alkali hydroxide. 2-(3-Phenoxy-phenyl)-propionic acid isthen obtained by distillation of the excess of the alcohol and byacidifying. The salt of the formed 2-(3-phenoxy-phenyl)-propionic acidmay be obtained by methods known per se. Alkali metal, alkali earthmetal and amine salts are preferably prepared. The calcium salt of thecompound is most preferred. If in the course of the reaction a salt of2-(3-phenoxy-phenyl)-propionic acid is obtained, then the free acid canbe set free from its salt.

The new compounds of the formula I and the C₁₋₆ alkyl ester of the new2-cyano-2-(3-phenoxy-phenyl)-acetic acid possess anti-inflammatoryactivity.

SPECIFIC EXAMPLES

The further details of the invention are illustrated by the followingExamples which serve merely for illustration and not for limitation.

EXAMPLE 1

A mixture of 189 g. of m-phenoxy-benzaldehyde and 1 liter of 1 molarisopropyl alcoholic aluminum isopropoxide solution is distilled understirring through a column as long as acetone may be detected in the cutby using 2,4-dinitro-phenyl-hydrazine. It takes about 2 to 3 hours. Therate of distillation is controlled so that within this time about 200 mlof distillate can be collected. The excess of isopropyl alcohol is thendistilled off in vacuo. To the residue 500 g. of ice and 550 ml. of 20%aqueous hydrochloric acid solution are added. The separated oil isshaken out with 2×1 liter of benzene and the benzene solution is driedabove sodium sulphate. When the benzene is distilled off 195 g. (97.4%)of m-phenoxy-benzyl alcohol is obtained, the purity of which is morethan 95% (determined by gas chromatography).

EXAMPLE 2

To a solution of 200 g. of m-phenoxy-benzyl alcohol in 1 liter of drychloroform 2 ml. of pyridine are added and a solution of 142.8 g.thionyl-chloride in 150 ml. of chloroform is added dropwise undercooling with ice water. When the addition is completed the cooling isterminated and the solution is allowed to warm up to room temperatureunder stirring and the temperature is maintained under stirring untilthe vigorous gas evolution ceases. The mixture is then boiled understirring until the gas evolution ceases completely. The solution is thenpoured into 2 liters of cold water, the chloroform layer is separatedand the aqueous layer is shaken out in 400 ml. of chloroform. Thecombined chloroform solutions are washed once with water and dried abovesodium sulphate. The drying agent is filtered off and chloroform isdistilled off; thus 210 g. (96%) of m-phenoxy-benzyl chloride areobtained, which can be distilled at 128° to 130° C. at a pressure of 0.3mmHg. Substantially no forerun and residue are obtained.

EXAMPLE 3

To a solution of 218 g. m-phenoxy-benzyl chloride in 850 ml. of 96%ethyl alcohol a solution of 57.8 g. of sodium cyanide in 100 ml. ofwater is added at once. The reaction mixture is boiled under stirringuntil the starting material cannot be detected anymore by thin layerchromatography. When the reaction is completed the reaction mixture ispoured into 1 liter of water and the separating oil is extracted with3×500 ml. of benzene. The combined benzene solutions are washed with 1liter of water and dried above sodium sulphate. Sodium sulphate isfiltered off and benzene is distilled off. 190 g. (91%) ofm-phenoxy-benzyl cyanide are obtained (purity more than 90%, determinedby gas chromatography). Boiling point 138° C./0.2 mmHg.

EXAMPLE 4

To a solution of 23 g. sodium in 500 ml. of anhydrous alcohol 209 g. ofm-phenoxy-benzyl cyanide and 260 g. of diethyl carbonate are added. Thereaction mixture is boiled under stirring for 2.5 hours, whereafter itis poured into 3.5 liter of water and acidified with 58 ml. of aceticacid. The separating oil is shaken out with 2×500 ml. of chloroform. Thecombined chloroform solutions are dried above sodium sulphate andevaporated. The oily residue consisting of2-(3-phenoxy-phenyl)-2-cyano-acetic acid ethyl ester is distilled invacuo, boiling point: 187°-192° C./0.2 mmHg; n_(D) ²⁷ : 1.5568.

Similarly, but substituting 183 g. of dimethyl carbonate for diethylcarbonate (3-phenoxy-phenyl)-cyano acetic acid is obtained (74%), b.p.:178°-182° C./0.2 mmHg; n_(D) ²⁵ : 1.5015.

EXAMPLE 5

To a solution of 23 g. of sodium in 500 ml. of anhydrous alcohol 209 g.of m-phenoxy-benzyl cyanide and 260 g. of diethyl carbonate are added.The reaction mixture is boiled under stirring for three hours and aftercooling 126 g. of dimethyl sulphate are added dropwise in portions andthe mixture is boiled under stirring for another 5 hours. The main partof the alcohol is distilled off and the residue is admixed with 3 litersof water. The 2-(3-phenoxy-phenyl)-2-cyano-propionic acid ethyl esterseparating in the form of oil is extracted with 3×500 ml. of benzene.The benzene solution is evaporated in vacuo after drying above sodiumsulphate. On the residue 250 ml. of methanol containing 15% ammonia ispoured and the mixture is maintained for 3 hours at a temperature of 90°to 100° C. in a bomb tube. The reaction mixture is processed as given inExample 6 and thus 220 g. (92.5%) of2-(3-phenoxy-phenyl)-2-cyano-propionic acid amide are obtained; m.p.128°-130° C.

EXAMPLE 6

A solution of 90 g. of 2-(3-phenoxy-phenyl)-2-cyano-propionic acid ethylester in 90 ml. of methanol containing 15% ammonia is maintained in abomb tube at 90°-100° C. for 3 hours. At this time the starting estercan no longer be detected by thin layer chromatography. The solution iscooled and the precipitating crystals are filtered by suction and dried.69 g. of (85%) 2-(3-phenoxy-phenyl)-2-cyano-propionic acid amide areobtained; m.p.: 128°-130° C. By evaporating the mother liquor further 11g. of the product are obtained; m.p.: 123°-125° C.

Total yield: 98.5%.

After recrystallization from 50% aqueous alcohol the product melts at134°-135° C.

Analysis: C₁₆ H₁₄ N₂ O₂ ; calculated: C%=72.16; H%=5.26; N%=10.52;found: C%=71.88; H%=5.40; N%=10.43.

NMR 1.9 ppm methyl: 3H, in CHCl₃ 6.15 ppm: NH₂ 2H, 6.7-7.5 ppm aromaticprotone: 9H.

According to the above procedure, but using 86 g. of2-(3-phenoxy-phenyl)-2-cyano propionic acid methyl ester,2-(3-phenoxy-phenyl)-2-cyano-propionic acid amide is obtained; m.p.:123°-125° C.

EXAMPLE 7

The same procedure is followed as in Example 6 but instead of beingheated the reaction mixture is allowed to stand in a closed vessel for48 hours at room temperature From 90 g. of2-(3-phenoxy-phenyl)-2-cyano-propionic acid ethyl ester 78 g. (96%)2-(3-phenoxy-phenyl)-2-cyano-propionic acid amide are obtained.

EXAMPLE 8

A mixture of 106.4 g. of 2-(3-phenoxy-phenyl)-2-cyano-propionic acidamide, 200 ml. of 40% aqueous sodium hydroxide and 400 ml. of alcohol isboiled under stirring for 20 hours. The alcohol is then distilled offand the residue is diluted with 200 ml. of water. The aqueous solutionis acidified to pH=1 by adding concentrated hydrochloric acid. Theseparating oil is extracted with 3×500 ml of benzene. The benzenesolution is evaporated after drying above sodium sulphate. Thus 96 g.(98.5%) 2-(3-phenoxy-phenyl)-propionic acid are obtained; the product issuitable for the preparation of salts without further purification.

EXAMPLE 9

90 g. of the crude 2-(3-phenoxy-phenyl)-propionic acid preparedaccording to Example 8 are dissolved in 740 ml. of 0.5 n sodiumhydroxide solution. The pH of the solution is 7 to 8. The solution istreated with decolorizing charcoal, 370 ml. of alcohol are added and themixture is heated to 70° C. At this temperature 100 ml. of 2 molaraqueous calcium chloride solution is added dropwise under stirringwithin 30 minutes. The solution containing the crystalline precipitateis allowed to cool to room temperature under stirring. The mixture isthen allowed to stand for a few hours in ice water, whereafter the whitecrystals are filtered by suction, washed with 2×100 ml. of 30% aqueousalcohol and air dried.

Thus 90 g. (86.5%) calcium salt of 2-(3-phenoxy-phenyl)-propionic acidare obtained; m.p.: 115°-120° C.

EXAMPLE 10

To a solution of 8.85 g. of sodium in 175 ml. of anhydrous alcohol 108.5g. of 2-(3-phenoxy-phenyl)-2-cyano-acetic acid ethyl ester and inportions 48.7 g. of dimethyl sulphate are added. The reaction mixture isstirred at room temperature until the exothermic reaction is completedwhereafter it is boiled for 5 hours. The reaction mixture is cooled andpoured into 2 liters of water. The separated oil is extracted with 3×250ml. of chloroform. The combined chloroform solutions are washed withwater and dried above sodium sulphate. The chloroform solution isevaporated and the residue consisting of2-(3-phenoxy-phenyl)-2-cyano-propionic acid ethyl ester is distilled invacuo. B.p.: 155°-157° C./0.05 mmHg; n_(D) ²⁵ : 1.5490.

When using 103 g. of m-phenoxy-phenyl-cyano acetic acid methyl ester asthe starting material 2-(3-phenoxy-phenyl)-2-cyano-propionic acid methylester is obtained, yield: 82.5%, b.p.: 174° C./0.1 mmHg; n_(D) ²⁶ :1.5520.

EXAMPLE 11

To a solution of 118 g. of 2-(3-phenoxy-phenyl)-2-cyano-propionic acidethyl ester in 226 ml. of ethyl alcohol 226 ml. of 10 n sodium hydroxidesolution is added and the reaction mixture is boiled under stirringuntil the gas evolution ceases. The alcohol is distilled off and theresidue is dissolved in water. The pH of the solution is adjusted to 1by adding concentrated hydrochloric acid. The separating oil isextracted with 2×100 ml. of benzene. The combined benzene solution isevaporated after drying above sodium sulphate and the residual2-(3-phenoxy-phenyl)-propionic acid is distilled in vacuo. B.p.:168°-171° C./0.1 mmHg.

When using 113 g. of 2-(3-phenoxy-phenyl)-2-cyano-propionic acid methylester as the starting material 2-(3-phenoxy-phenyl)-propionic acid ofthe same physical properties is obtained.

EXAMPLE 12

One may proceed as described in Example 10, but dimethyl sulphate isreplaced by 88 g. of methyl iodide. The obtained product is identicalwith the product prepared according to Example 10.

EXAMPLE 13

To a solution of 23 g. of sodium in 500 ml. of anhydrous alcohol 209 g.of m-phenoxy-benzyl cyanide and 145 g. of diethyl carbonate are added.The reaction mixture is boiled under stirring and after cooling 126 mg.of dimethyl sulphate are added dropwise in portions and the mixture isboiled under stirring for a further 5 hours. To the reaction mixture 500ml. of 10 n sodium hydroxide solution is added and the mixture is boiledunder stirring until the gas evolution ceases. When the reaction iscompleted the alcohol is distilled off. The residue is dissolved inwater. The pH of the solution is adjusted to 1 by adding concentratedhydrochloric acid. The separated oil is taken up in 500 ml. of benzene.The benzene solution is evaporated after drying above sodium sulphateand the residual 2-(3-phenoxy-phenyl)-propionic acid is distilled off.B.p.: 168°-171° C./0.1 mmHg. Yield: 206 g. (85%).

What we claim is:
 1. A process for the preparation of2-cyano-2-(3-phenoxy-phenyl)-propionic acid amide which comprises thesteps of:(a) reacting m-phenoxy-benzyl cyanide with a C₁ to C₆ dialkylcarbonate in the presence of a basic catalyst to obtain a2-cyano-2-(3-phenoxy-phenyl)-acetic acid C₁ to C₆ alkyl ester; (b)methylating the 2-cyano-2-(3-phenoxy-phenyl)-acetic acid C₁ to C₆ alkylester to yield a 2-(3-phenoxy-phenyl)-2-cyano-propionic acid C₁ to C₆alkyl ester; and (c) reacting the 2-(3-phenoxy-phenyl)-2-cyano-propionicacid C₁ to C₆ alkyl ester with a compound suitable for the introductionof an amino group into the molecule to yield the desired product.
 2. Theprocess defined in claim 1, step (a), wherein the compound suitable forthe introduction of an amino group is ammonia.
 3. The process defined inclaim 1 which comprises preparing the2-cyano-2-(3-phenoxy-phenyl)-propionic acid amide without isolation ofthe intermediate products.
 4. The process defined in claim 1, step (a),wherein m-phenoxy-benzyl cyanide is reacted with diethyl carbonate inthe presence of a sodium alcoholate.
 5. The process defined in claim 4wherein the sodium alcoholate is sodium ethylate.
 6. The process definedin claim 1, step (b), wherein the 2-cyano-2-(3-phenoxy-phenyl)-aceticacid C₁ to C₆ alkyl ester is methylated with methyl iodide or dimethylsulfate.
 7. 2-cyano-2-(3-phenoxy-phenyl)-propionic acid amide.